Active-site-directed 3D database searching: Pharmacophore extraction and validation of hits |
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| Authors: | David E Clark David R Westhead Richard A Sykes Christopher W Murray |
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| Institution: | (1) Proteus Molecular Design Ltd., Proteus House, Lyme Green Business Park, SK11 0JL Macclesfield, Cheshire, U.K.;(2) Present address: Dagenham Research Centre, Rhône-Poulenc Rorer Ltd., Rainham Road South, RM10 7XS Dagenham, Essex, U.K.;(3) Present address: EMBL Outstation, European Bioinformatics Institute, Hinxton Hall, CB10 1RQ Hinxton, Cambridge, U.K. |
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| Abstract: | Summary Two new computational tools, PRO_PHARMEX and PRO_SCOPE, for use in active-site-directed searching of 3D databases are described. PRO_PHARMEX is a flexible, graphics-based program facilitating the extraction of pharmacophores from the active site of a target macromolecule. These pharmacophores can then be used to search a variety of databases for novel lead compounds. Such searches can often generate many  hits of varying quality. To aid the user in setting priorities for purchase, synthesis or testing, PRO_SCOPE can be used to dock molecules rapidly back into the active site and to assign them a score using an empirical scoring function correlated to the free energy of binding. To illustrate how these tools can add value to existing 3D database software, their use in the design of novel thrombin inhibitors is described. |
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| Keywords: | Drug design Lead generation Thrombin inhibitors Scoring function |
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